Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease that predominantly affects women of childbearing age. LAM is characterized by proliferation of abnormal smooth muscle-like cells in nodules in the lung parenchyma and other sites, and by cystic changes with lung tissue destruction. LAM occurs in 30-40% of women with tuberous sclerosis complex (TSC). LAM can also occur as a sporadic disease in women who do not have generalized features of TSC. TSC is due to germline mutations in either TSC1 or TSC2, and similar inactivating somatic mutations are found in LAM cells from sporadic LAM patients.
About 60% of women with the sporadic form of LAM also have renal angiomyolipomas. The presence of TSC2 mutations in LAM cells and renal angiomyolipoma cells from women with sporadic LAM, but not in normal tissues, has led to the model that LAM cells spread to the lungs via a metastatic mechanism. Genetic analyses of recurrent LAM after lung transplantation also support the metastatic model for LAM pathogenesis. The only treatment for end-stage LAM and respiratory failure is lung transplantation, with its intrinsic limitations. Furthermore LAM can recur in the transplanted lungs.
LAM cells typically have inactivating TSC2 mutations and mTORC1 activation. However, clinical response to mTORC1 inhibitors has been limited. Accordingly, there is an unmet need for new treatments for LAM.